PROJECT SUMMARY With greater numbers of older individuals living with HIV, vulnerability to HIV-Associated Non-AIDS (HANA) conditions and age-related deterioration have emerged as important clinical, public health, and research concerns. Studies suggest that HIV, directly or indirectly, accelerates aging processes with putative pathways involving chronic immune activation, inflammation, and oxidative stress leading to cellular senescence and increased vulnerability for HANA. More recently, epigenetic-based methods for determining cellular aging been developed to measure ?biological age? using DNA methylation information at a number of CpG sites. A study of non-Hispanic white men that used quantification of DNA methylation, an epigenetic signal to determine cellular aging, found that the biological age of HIV-infected men was 4.9 years ahead of their chronological age. In contrast, the biological and chronological ages of the HIV-uninfected men were similar. Data are lacking for non-whites, women, and the older ages of the spectrum of people living with HIV. Although changes in DNA methylation and epigenetic age acceleration are associated with the frailty phenotype and other age related functional deterioration, this has not been well examined among older HIV Infected individuals. Nor have the roles of inflammation and oxidative stress, which are putatively involved in alterations in DNA methylation and are elevated among people living with HIV, been evaluated in relation to epigenetic age among older adults. Therefore, we propose a focused cross-sectional study of 4 groups of African American (AA) men and women (HIV-infected and uninfected adults ?60 years, stratified by frailty status) designed to determine if HIV is associated with accelerated biological aging among older AA adults, whether biological age acceleration is related to geriatric outcomes, and whether monocyte activation or oxidative stress is associated with biological aging. We hypothesize that biological age as measured by DNA methylation will be greater in HIV-infected than uninfected AA adults and that biological age will be associated with frailty and cognitive function. Lastly, we hypothesize that monocyte immune activation and increased levels of oxidative stress are independently associated with biological age in HIV-infected and uninfected older AA adults (?60 years). The following are the specific aims: (1) Assess if HIV infection is associated with biological age advancement as measured by DNA methylation in older AA adults; (2) Evaluate if biological age advancement as measured by DNA methylation is associated with frailty in older AA adults, and if this association is different in those with and without HIV; (2a) Evaluate if biological age advancement as measured by DNA methylation is associated with cognitive function in older AA adults, and if this association is different in those with and without HIV, and; (3) Explore if immune activation and oxidative stress are independently associated with biological age as measured by DNA methylation in older AA adults with and without HIV.